Phylogenetic reduction of the magnocellular red nucleus in primates and inter-subject variability in humans.

Introduction: The red nucleus is part of the motor system controlling limb movements. While this seems to be a function common in many vertebrates, its organization and circuitry have undergone massive changes during evolution. In primates, it is sub-divided into the magnocellular and parvocellular parts that give rise to rubrospinal and rubro-olivary connection, respectively. These two subdivisions are subject to striking variation within the primates and the size of the magnocellular part is markedly reduced in bipedal primates including humans. The parvocellular part is part of the olivo-cerebellar circuitry that is prominent in humans. Despite the well-described differences between species in the literature, systematic comparative studies of the red nucleus remain rare. Methods: We therefore mapped the red nucleus in cytoarchitectonic sections of 20 primate species belonging to 5 primate groups including prosimians, new world monkeys, old world monkeys, non-human apes and humans. We used Ornstein-Uhlenbeck modelling, ancestral state estimation and phylogenetic analysis of covariance to scrutinize the phylogenetic relations of the red nucleus volume. Results: We created openly available high-resolution cytoarchitectonic delineations of the human red nucleus in the microscopic BigBrain model and human probabilistic maps that capture inter-subject variations in quantitative terms. Further, we compared the volume of the nucleus across primates and showed that the parvocellular subdivision scaled proportionally to the brain volume across the groups while the magnocellular part deviated significantly from the scaling in humans and non-human apes. These two groups showed the lowest size of the magnocellular red nucleus relative to the whole brain volume and the largest relative difference between the parvocellular and magnocellular subdivision. Discussion: That is, the red nucleus has transformed from a magnocellular-dominated to a parvocellular-dominated station. It is reasonable to assume that these changes are intertwined with evolutionary developments in other brain regions, in particular the motor system. We speculate that the interspecies variations might partly reflect the differences in hand dexterity but also the tentative involvement of the red nucleus in sensory and cognitive functions.

Logical negation mapped onto the brain.

High-level cognitive capacities that serve communication, reasoning, and calculation are essential for finding our way in the world. But whether and to what extent these complex behaviors share the same neuronal substrate are still unresolved questions. The present study separated the aspects of logic from language and numerosity-mental faculties whose distinctness has been debated for centuries-and identified a new cytoarchitectonic area as correlate for an operation involving logical negation. A novel experimental paradigm that was implemented here in an RT/fMRI study showed a single cluster of activity that pertains to logical negation. It was distinct from clusters that were activated by numerical comparison and from the traditional language regions. The localization of this cluster was described by a newly identified cytoarchitectonic area in the left anterior insula, ventro-medial to Broca's region. We provide evidence for the congruence between the histologically and functionally defined regions on multiple measures. Its position in the left anterior insula suggests that it functions as a mediator between language and reasoning areas.

Cytoplasmic TERT Associates to RNA Granules in Fully Mature Neurons: Role in the Translational Control of the Cell Cycle Inhibitor p15INK4B.

The main role of Telomerase Reverse Transcriptase (TERT) is to protect telomere length from shortening during cell division. However, recent works have revealed the existence of a pool of TERT associated to mitochondria, where it plays a role in survival. We here show that in fully differentiated neurons the largest pool of cytoplasmic TERT associates to TIA1 positive RNA granules, where it binds the messenger RNA of the cyclin kinase inhibitor p15INK4B. Upon stress, p15INK4B and TERT dissociate and p15INK4B undergoes efficient translation, allowing its pro-survival function. These results unveil another mechanism implicated in the survival of fully differentiated neurons.

Regulation of tyrosine kinase B activity by the Cyp46/cholesterol loss pathway in mature hippocampal neurons: relevance for neuronal survival under stress and in aging.

It is well established that memory formation and retention involve the coordinated flow of information from the post-synaptic site of particular neuronal populations to the nucleus, where short and long-lasting modifications of gene expression occur. With age, mnemonic, motor and sensorial alterations occur, and it is believed that extra failures in the mechanisms used for memory formation and storage are the cause of neurodegenerative pathologies like Alzheimer's disease. A prime candidate responsible for damage and loss of function during aging is the accumulation of reactive oxygen species, derived from normal oxidative metabolism. However, dysfunction in the aged brain is not paralleled by an increase in neuronal death, indicative that the brain is better suited to fight against the death signals generated from reactive oxygen species than against loss-of-function stimuli. A main aim of this laboratory is to understand how neurons perform and survive in the constitutive stress background represented by aging. In this report, we summarize our recent findings in relation to survival.

Oxidative stress activates the pro-survival TrkA pathway through membrane cholesterol loss.

Neuronal activity is a highly demanding energetic process, resulting in the gradual accumulation of reactive oxygen species (ROS). Despite comparatively weak anti-oxidant defence systems, neurons outlive the pressure of ROS by activating most robust anti-stress mechanisms. We recently showed that one such mechanism is the activation of the TrkB receptor pathway, in turn determined by the loss of membrane cholesterol. It is not known however what causes the loss of membrane cholesterol. We here show that in differentiated PC12 cells induction of ROS is paralleled by a moderate loss of membrane cholesterol and the activation of the pro-survival TrkA receptor. Pharmacological reduction of cholesterol in non-stressed cells triggers TrkA activation while cholesterol replenishment inhibits receptor activation induced by stress. Moreover, addition of a ROS inhibitor prevented cholesterol loss and receptor activation under stress. These results highlight cholesterol loss as a compensatory protective mechanism against acute stress.